The thioredoxin peroxidases represent a group of recently identified components of the antioxidative network, which reduce H2O2 and organic peroxides using thioredoxin as an electron source. These ubiquitous species are thought to play a particularly critical role in insects, given the lack of glutathione peroxidase activity in these animals. The purpose of the present study is to determine if the enhancement of thioredoxin peroxidase activity would lower the level of oxidative stress, thereby slowing the rate of the aging process, while a reduction in activity would increase the level of oxidative stress and accelerate the rate of aging. The specific focus of this study will be two distinct thioredoxin peroxidase genes, which are expressed at high levels in the adult tissues of Drosophila melanogaster. One of them has been localized to the mitochondria (DPx-5037), while the other has been identified as a secreted form (DPx-4 156). Reduction in thioredoxin peroxidase activity will be accomplished in Drosophila by under-expression, through RNA interference and/or the through the use of mutant alleles isolated by standard genetic approaches. Enhancement of thioredoxin peroxidase activity will be accomplished by over-expression by transgenic methodology, either using transgenes under control of the native promoters or engineered to be inducible by antibiotic administration. The effects of over- and under-expresssion of these genes on life span and a variety of biochemical/physiological alterations related to the aging process will be determined. Results should (i) provide a direct test of the role of the thioredoxin peroxidases in the aging process, (ii) permit further assessment of the validity of the oxidative stress hypothesis of aging, and (iii) aid in the design of similar studies in mammals.